Project 4: Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles Junior Investigator: Thomas Werfel Mentor: Adam Smith, University of Mississippi Efferocytosis, the phagocytic clearance of apoptotic cells, in the tumor microenvironment promotes immunosuppression, dampening anti-tumor immunity and thus the therapeutic response to cytotoxic and immunotherapies. Macrophages are primarily responsible for efferocytosis in the tumor microenvironment, where they recognize apoptotic cells using the phosphatidylserine receptor MerTK and then produce a host of immunosuppressive signals in response to apoptotic cell engulfment. Attempts to block efferocytosis in the tumor microenvironment by inhibiting the activity of MerTK show promise. However, chronic, systemic blockade of MerTK and/or hypomorphic MerTK mutations contribute to inflammation-related retinopathies, lupus-like auto- immunity, and risk of auto-immunity. To circumvent the deleterious effects of auto-immunity associated with chronic systemic inhibition, we propose to target MerTK specifically within tumor-associated macrophages (TAMs) using high-mannose decorated-nanoparticles (hmn-NPs) harboring a MerTK inhibitor. We propose novel synthetic strategies to produce nanoparticles with 1) a polypropylene sulfide core for hydrophobic drug loading and targeted release and 2) a glycopolymer-based corona consisting of a mixture of trehalose and mannose polymers. Trehalose has been shown to impart enhanced stability to drug delivery vehicles and will be crucial for endowing the stability necessary for systemic delivery applications. Mannose has been used to target nanoparticles to TAMs because of their characteristic overexpression of the mannose receptor. However, past strategies have been limited to local delivery applications and have employed monomeric versions of mannose. Our polymeric version of mannose will more closely mimic the natural binding partners for mannose receptor, mannan and high-mannose glycans, which have much higher affinity than monomeric mannose. Thus, a major goal of this project is to rigorously compare the effectiveness of monomeric mannose and polymannose as targeting strategies for TAMs. Using the TAM-targeting hmn-NPs as an enabling technology, we will test the therapeutic impact of TAM-specific MerTK inhibition on immunosuppression in the tumor microenvironment, tumor progression, and systemic auto-immunity.